Sofosbuvir, L-Alanine, N-[[P(S),2′R]-2′-deoxy-2′-fluoro-2′-methyl-P-phenyl-5′-uridylyl]-, 1-methylethyl ester, or (2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, having the following formula,
is an orally available, second generation uridine nucleoside analogue which inhibits the NS-5 protein of hepatitis C virus (HCV). Sofosbuvir and its isomer act as prodrugs and are converted through a series of in vivo transformations to an active triphosphate metabolite.
Sofosbuvir is marketed under the registered trademark SOVALDI®. SOVALDI® is available as immediate release tablets. Each tablet contains 400 mg of sofosbuvir. The active ingredient load in SOVALDI® tablets is about 30% and the tablets also contains glidant. More specifically, the SOVALDI® tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. WO 2013/082003 and WO 2014/120981 also describes tablets containing sofosbuvir.
Sofosbuvir is described in U.S. Pat. No. 7,964,580 and in U.S. Pat. No. 8,334,270. Solid state forms of Sofosbuvir are described in WO 2010/135569, US 2011/251152, WO 2011/123645 and CN 104130302. CN 104277088 and CN 104447924 also describe crystalline forms of sofosbuvir.
Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis—“TGA,” or differential scanning calorimetry—“DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state (13C—) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
US 2011/251152 describes a number of crystalline forms of Sofosbuvir, i.e. forms 1, 2, 3, 4, 5 and 6, which are characterised by X-ray powder diffraction (XRPD) peaks, as well as an amorphous form. According to this publication, crystalline forms 2, 3, 4 and 5 of Sofosbuvir are said to be prepared by crystallisation from dichloromethane, chloroform, acetonitrile and anisole. However, following filtration and/or drying, these crystalline forms convert to Form 1.
CN 104130302 describes crystalline sofosbuvir form A characterised by XRD Form A is described as a non-solvated, non-hydrated form. The Form A is prepared by dissolving Sofosbuvir in a solvent and adding an antisolvent and allowing the mixture to stand in a sealed vessel for 15-24 hours under certain conditions. The solvent/antisolvent combinations include anhydrous ethanol and one of isopropyl ether, cyclohexane, n-pentane, or toluene or the solvent/anti-solvent may be acetone/n-pentane, acetone/petroleum ether or ethyl acetate/petroleum ether.
Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For example it has now been found that Form 6 of Sofosbuvir has a high propensity to become electrostatically charged. Electrostatically charged active pharmaceutical ingredients may display poor flowability and/or a tendency to sticking, and thus ultimately may result in difficulties during the operations of the manufacturing process of a pharmaceutical composition based on such an electrostatically charged active pharmaceutical ingredient. Moreover poor content uniformity may be observed in the final dosage form when a dry process such as, for example, dry compression is used to make a pharmaceutical composition with an electrostatically charged active pharmaceutical ingredient. For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Sofosbuvir.
Additionally, the prior art processes for producing crystalline forms of Sofosbuvir, such as those described above, are generally impractical for medium to large scale preparation. Moreover, the resulting products may suffer from polymorphic transformations, which can lead to polymorphically impure materials. Therefore, there is a need in the art to provide further processes for preparing solid state forms of Sofosbuvir.
The present invention aims to provide a new crystalline form of Sofosbuvir, as well as new processes for preparing crystalline forms of Sofosbuvir. In particular, the processes of the present invention enable the production of Form 7 of Sofosbuvir, which may be substantially free of other solid state forms of Sofosbuvir. The processes described herein enable the consistent production of these forms of Sofosbuvir which can be used on a large scale. The present processes also seeks to avoid the need to use a number of different organic solvents, which may cause undesirable and unpredictable polymorphic transformations, and which may lead to the production of mixtures of different crystalline forms, and moreover may introduce undesirable impurities into the product.